Summary of Work: The glucocorticoid hormone action group studies how environmental stressors elicit and transmit metabolic signals. Our primary interest is in steroid receptor signalling, adaptation to chronic environmental stress as well as the development of resistance to glucocorticoids. Recent studies in our lab have shown that a mutual antagonism exists between pro-inflammatory cytokines and glucocorticoids. Specifically signal transduction by the glucocorticoid receptor is impaired in cells with active nuclear NfKB, and signal transduction by NfKB is impaired in cells with active nuclear glucocorticoid receptor. We are studying the mechanism of this antagonism and evaluating if NfKB is a generalized endocrine disruption. A second area of effort is aimed at understanding what role phosphorylation has in glucocorticoid receptor signal transduction. Glucocorticoid receptors are phosphoproteins, but there is currently little information on how phosphorylation affects receptor function. The function of phosphomutant receptors in terms of transcriptional activation and repression is being evaluated. Another focus of our work is on glucocorticoid receptor down regulation which leads to resistance to steroids. We have shown that the glucocorticoid receptor represses the expression of its own gene. This repression occurs via a consequence of the direct interaction of the glucocorticoid receptor with two intragenic binding sites within the gene. These sites have been mapped, functionally evaluated, and mutant receptors are being studied. We have recently described the widespread expression of a second form of human glucocorticoid receptor. This receptor, termed hGRBeta, is an alternatively spliced product from the same gene and functions as a strong dominant negative inhibitor of glucocorticoid receptor signalling. This receptor shows strong expression in epithelia cells and may be important in environmental diseases such as asthma.